The goal of these experiments is to understand the processing of visual information in primate retinas. The focus in this grant period will be on midget ganglion cells, which mediate both high acuity vision and red-green color vision. Midget ganglion cells are the most common type in primate retinas, but despite many years of research, a number of important questions about the neural circuit providing their input remain unanswered. Two of these questions will be addressed in the proposed anatomical experiments. The first question deals with the source of the input from rods to midget ganglion cells. It is uncertain whether midget ganglion cells receive highly-sensitive input from rods via synapses from local circuit neurons, AII amacrine cells, onto midget bipolar cells and if so, where in the retina this first appears. Midget bipolar cells and AII amacrine cells will be labeled using whole mount preparations of macaque retina, and their contacts will be labeled using a third marker for either chemical or electrical synapses. The working hypothesis is that these synapses appear just outside the rod-free, central fovea. An alternative hypothesis is that central midget ganglion cells receive rod input only via relatively insensitive rod-cone gap junctions, but peripheral midget ganglion cells receive more sensitive rod input via AII cells. The second question deals with neural circuit that generates opposing responses of midget ganglion cells to stimulation of red and green cones. In the central retina, the excitation is selective because midget ganglion cells receive input from a single red or green cone via a single midget bipolar cell. But it is uncertain how selective excitation would be generated in the periphery, where midget ganglion cells receive input from more than one midget bipolar cell. It is unclear how selective inhibition arises anywhere in the retina because the inhibitory local circuit neurons, horizontal cells and amacrine cells, are unselective in their connections. The working hypothesis to account for the selectivity of midget ganglion cell responses is based on results from physiological experiments in other mammalian retinas and a linear model of the neural circuit developed during the last grant period. According to the model, amacrine cells with relatively narrow dendritic fields and branches throughout the inner plexiform layer make the responses of midget ganglion cells more specific than would be predicted by the distribution of the red and green cones. Although individual amacrine cells use the inhibitory neurotransmitter glycine and are unselective in their connections, their net effect is to enhance excitation of the midget ganglion cell in response to stimulation of one cone type. The working hypothesis is that the underlying mechanism is inhibition of a tonic, inhibitory input by a second type of amacrine cell. This hypothesis will be tested by identifying the glycinergic amacrine cells presynaptic to midget bipolar cells and midget ganglion cells and studying their interactions with other amacrine cells in the circuit. Because the retinas of humans and macaques are so similar, the results of the proposed experiments would be relevant to human vision. PUBLIC HEALTH RELEVANCE: This research deals with the neural circuit that generates the light responses of midget ganglion cells. These are, by far, the most common type of ganglion cells in humans and other primates, and they mediate both high acuity vision and red-green color vision. The experiments on the origin of rod inputs to midget ganglion cells would help to understand vision in dim light, when both rods and cones are active. In the United States, this is particularly important for driving at night, and problems with vision in dim light are an early sign for many eye diseases. These experiments would also help to explain the mechanism underlying the electroretinogram, a widely-used method to diagnose eye diseases and monitor the effects of treatments.